1. Field of the Invention
This invention relates to a method of converting 9-dihydro-13-acetylbaccatin III to 10-deacetylbaccatin III.
2. Discussion of the Prior Art
Many taxanes, e.g. paclitaxel and docetaxol are being aggressively studied and tested for use as cancer treating agents. As described in many publications such as Canadian Patent Application No. 2,188,190, published Apr. 18, 1998 in the name of Zamir et al, which is incorporated herein by reference, the taxanes are active in various tumor systems. Taxanes are substances occurring naturally in yew trees such as Taxus canadensis, which is common in Eastern Canada and the United States. One of the chemicals extracted from the needles of Taxus canadensis is 9-dihydro-13-acetylbaccatin III, which is used to produce, inter alia, 10-deacetylbaccatin IIIxe2x80x94a useful intermediate for the preparation of paclitaxel and analogues thereof.
Various methods of converting 9-dihydro-13-acetylbaccatin III into 10-deacetylbaccatin III have been proposed (see, for example the above mentioned CA 2,188,190). However, it has been found that such methods result in poor yields of finished product. Thus, a need still exists for an efficient method for converting 9-dihydro-13 acetylbaccatin III to 10-deacetylbaccatin III (DAB III).
The object of the present invention is to meet the above defined need by providing a relatively efficient method of converting 9-dihydro-13-acetylbaccatin III to DAB III.
Accordingly, the invention relates to a method of converting 9-dihydro-13-acetylbaccatin III into 10-deacetylbaccatin III comprising the steps of
(a) protecting the C-7 group of 9-dihydro-13-acetylbaccatin III by replacing the C-7 hydroxyl group with a protecting group;
(b) oxidizing the C-9 hydroxyl group in the resulting product to produce a C-9 ketone; and
(c) deprotecting the C-9 ketone to form 10-deacetylbaccatin III.
The first step in the method of the present invention involves the dissolving of 9-dihydro-13-acetylbaccatin III in dry solvent such as CH2Cl2, CHCl3, THF, Et2O or Bz. A dry base, e.g. pyridine, TEA or NaHCO3 and/or a catalytic amount of p-N,N-dimethylaminopyridine (DMAP) is added to the solution, followed by 1-6 equivalents of a protecting reagent (TMSCl, TESCl or Ac2O) at a temperature of between room temperature and xe2x88x9278xc2x0 C. The mixture is stirred continuously for 0.5-6 hours before being quenched by the addition of water. The mixture is poured into ethyl acetate and washed sequentially with dilute acid, water and brine, and dried over magnesium sulfate. The solution is evaporated under vacuum to give a crude solid (7-OH protected-9-baccatin III up to 91% yield)
A 3,5-disubstituted pyrazole such as 3,5-dimethyl-pyrazole is added to a suspension of metal oxide, e g. chromium trioxide (2-20 equivalents) in a solvent. Suitable solvents include CH2Cl2, CHCl3, THF, Et2O and Bz. The mixture is stirred at room temperature for at least 15 minutes. A 7-OH protected 9-dihydro-13-acetylbaccatin III in the same solvent is added to the solution in one portion, and the mixture is stirred for 0.5 hour to one week to produce a C-9 ketone in up to 90% yield.
The C-9 ketone is dissolved in a suitable organic solvent such as an alcohol, an ether, CH2Cl2 or CHCl3 with or without water, and reacted with an acid, a base, or a strong nucleophile, such as a bicarbonate, a carbonate, ammonia, an amine, a hydrazine, a hydroxide, a hydroperoxide or an alyllithium. The reaction mixture thus produced is stirred at a controlled temperature (0xc2x0 C. to solvent reflux). The reaction is monitored by thin-layer chromatography until it has progressed satisfactorily. Routine liquid extraction is performed followed by solvent evaporation to produce crude 10-deacetylbaccatin III in up to 85% yield.
The reaction scheme for the above described general procedure is as follows 
In accordance with a preferred embodiment of the invention, R in the above formula is an acetyl group. The reaction scheme for the preferred embodiment is as follows 